The invention relates to peptidomimetic compounds which are novel analogs of glutathione. The invention also relates to pharmaceutical compositions comprising such glutathione analogs. The novel analogs are useful as inhibitors of glutathione S-transferase, in particular of GST P1-1. Such inhibition has beneficial effects in chemotherapy.
The tripeptide glutathione (GSH), xcex3-glu-cys-gly, plays a critical role in the cellular protection against potentially harmful electrophiles from xenobioytic sources or those generated by endogenous oxidative processes. GSH-conjugates are formed by nucleophilic attack of the cystein sulfhydryl on the electrophilic center of a suitable substrate. This process is catalysed by glutathione-S-transferase (GST). Several members of the GST-isoenzyme family are involved in conjugation of drugs and thereby in drug resistance. GST inhibitors may be used to improve drug response and decrease drug resistance. In particular isoenzyme selective GST inhibitors may be of use. Conjugates of GSH and their cell-permeable esterified derivatives are effective competitive inhibitors of GST.
WO95/08563 discloses tripeptide compounds which are analogs of GSH. They are generally inhibitors of GST-activity and the various compounds contained in this group show diverse specificities with respect to GST-isoenzymes. Disclosed are symmetrical esters of 1 to 10C units, with the diethyl ester as the preferred embodiment. In WO00/44366 essentially the same compounds are used, in this disclosure however lipid formulations of diesters with a greater lipophilicity than the corresponding diethylester are preferred. WO95/09866 discloses the tripepitide analogs of GSH modified on the cysteine thiol groups with cytotoxic compounds, in particular phosphorodiamidate. The contents of WO95/08563, WO00/44366 and WO95/09866 are incorporated herein by reference.
GST isoenzymes are classified in a single microsomal subclass and three cytosolic subclasses xcex1, xcexc and xcfx80. These classes show differences in structure, immunological activity, substrate specificity and inhibitor sensitivities.
The GST xcfx80 isotype has been associated with tumors, including cancers of the colon, stomach, pancreas, uterine cervix, renal cortex, adenocarcinoma of the breast and lung, nodular small cell lymphoma, mesothelioma, small cell and non-small cell lung carcinoma and bladder carcinoma as well as in chronic lymphocytic leukemia (CLL). In particular the enzyme GST P1-1 is over-expressed in many types of human cancers. Elevated GST P1-1 levels also are correlated with the development of resistance to many commonly used chemotherapeutic drugs.
Myelodysplastic syndrome (MDS) is a bone narrow disorder characterized by abnormal production of white blood cells. Animals that lack GST P1-1 activity exhibit higher than normal levels of white blood cells, suggesting that inhibition of the GST P1-1 activity might cause a similar effect. Simulation of white blood cell production by inhibition of GST P1-1 may provide the basis for a treatment of MDS as well as for other hemoatologic conditions associated with low white blood cell levels.
A disadvantage of the known GSH conjugates is their sensitivity towards peptidase-mediated breakdown which results in loss of inhibitory action of the conjugates. Enzymatic cleavage hampers or even obstructs therapeutic use of GSH conjugates. In particular the xcex3-glutamyl-cysteine peptide bond in the GSH conjugates is sensitive towards xcex3-glutamyl transpeptidase (xcex3GT).
It is an object of the present invention to provide metabolically stable GST inhibitors. It is in particular the object to provide compounds that are stable towards enzymatic breakdown or cleavage.
A further objective is to provide GST isoenzyme selective inhibitors, in particular selective for the GST xcfx80 subclass.
Surprisingly it has been found that compounds as defined in the appending claims meet these objectives. Thus the invention relates to a compound of formula 
wherein
Zxe2x95x90CH2 and Yxe2x95x90CH2, or
Zxe2x95x90O and Yxe2x95x90Cxe2x95x90O,
R1 and R2 are independently selected from group consisting of H, linear or branched alkyl (1-25C), aralkyl (6-26C), cycloalkyl (6-25C), heterocycles (6-20C), ethers or polyethers (3-25C), and where R1-R2 together have 2-20C atoms and form a macrocycle with the remainder of formula I;
R3 is selected from the group consisting of H and CH3,
R4 is selected from the group consisting of 6-8C alkyl, benzyl, naphthyl and a therapeutically active compound, and
R5 is selected from the group consisting of H, phenyl, CH3 and CH2phenyl or a pharmaceutically acceptable salt thereof.
In a preferred embodiment R3 in the formula above is H. In a further preferred embodiment R4 in the formula above is benzyl. In yet a further preferred embodiment R5 in the formula above is phenyl.
Further the invention relates to the compound of formula 
wherein
R1 and R2 are independently selected from the group consisting of H, linear or branched alkyl (1-25C), aralkyl (6-26C), cycloalkyl (6-25C), heterocycles (6-20C), ethers or polyethers (3-25C), and where R1-R2 together have 2-20C atoms and form a macrocycle with the remainder of formula I; or a pharmaceutically acceptable salt thereof.
And further the invention relates to the compound of formula 
wherein
R1 and R2 are independently selected from the group consisting of H, linear or branched alkyl (1-25C), aralkyl (6-26C), cycloalkyl (6-25C), heterocycles (6-20C), ethers or polyethers (3-25C), and where R1-R2 together have 2-20C atoms and form a macrocycle with the remainder of formula I; or a pharmaceutically acceptable salt thereof.
Preferably the peptidomimetic compounds of the invention have the stereochemistry depicted in formula 
Also the invention concerns pharmaceutical compositions comprising a compound of the above formulas.
The invention also relates to a method for the treatment of cancer in which a peptidomimetic compound according to this invention is used.